Diabetic nephropathy (DN) is characterized by increased urinary albumin excretion and declined renal function. Changes in albumin excretion are considered the hallmark of the onset or progression of DN. However, some diabetic patients have advanced changes in renal pathology and progressive decline in kidney function even though their urine albumin levels are in the normal range. This limits albumin excretion as an accurate surrogate marker for renal function decline. Although several urine-based proteins have emerged as potential markers of DN, none of them have been used clinically. Water channel AQP5 functions in the generation of saliva, tears, and pulmonary secretions, but is barely detectable in normal kidneys. We hypothesize that AQP5 is a novel urine marker of DN and can improve the prediction of DN progression. We have reported detectable AQP5 in the kidney biopsies from 17/17 patients with DN and 0/15 normal controls. We also have found AQP5 in kidney biopsies from 10/10 patients with chronic kidney disease of unknown cause. Moreover, our preliminary data show that urine AQP5 1) is significantly higher in DN than in DM and normal controls, and in DN stage V than in stage III; 2) correlates with serum creatinine, urine microalbumin, and multiple other known risk factors of DN; 3) improves the clinical models in distinguishing DN from normal controls and DM; and 5) has a high stability over prolonged frozen storage. Our preliminary study is limited due to exclusion of children and young adults, and a lack of analyses of daily variation of urine AQP5 and longitudinal samples. Hence, we propose to measure urine AQP5 in 3 first-morning void urine samples from each of 170 subjects. They are >6 years old and consist of normal controls and patients with either DM or DN at various stages. We will also measure AQP5 in a urine repository from a multinational clinical trial with >1000 DN patients. These patients have prospectively followed up for up to 2 years. We will focus on the 60 progressors and 60 carefully-matched non-progressors. Multiple logistic regression, ROC, ANOVA, and other statistical analyses will be performed. We expect that urine AQP5 will increase the sensitivity and specificity of clinical models in distinguishing DN from DM and normal controls and improve prediction of DN progression. Our study thus addresses important clinical and translational questions and are potentially of high clinical and public health impact. It is novel since neither AQP5 as a marker of any disease nor AQP5 urine test has never been reported. It may result in development of a new urine test that allows identification and close surveillance of individuals at risk, prediction of DN progression, and thu reduction of the medical costs. If successful, this project may lay a solid foundation of full-scal clinical studies with subjects including those in other clinical settings such as acute kidney injuy and chronic kidney disease of unknown etiology to determine the true broad clinical utility and the spectrum validity and specificity of AQP5 as a novel diagnostic and prognostic marker for DN.